Total Syntheses of (+)-Zampanolide and (+)-Dactylolide Exploiting a Unified Strategy

Smith, Amos B.; Safonov, Igor G.; Corbett, R. Michael

doi:10.1021/ja020635t

Cited by 173 publications

(140 citation statements)

References 66 publications

(74 reference statements)

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“…Although hemiaminals are in general not stable under aqueous conditions, a few carbinolamide-bearing natural products have been identified, such as the echinocandin type anti-fungal antibiotics anidulafungin (known as Eraxis) (23) and micafungin (known as Mycamine) (24), spergualin (25), zampanolide (26), bicyclomycin (Bicozamycin) (27)(28)(29), epolactaene (30), and oteromycin (31) (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of tlmK Unveiling Unstable Carbinolamide Intermediates in the Tallysomycin Biosynthetic Pathway

Wang

Tao

Wendt-Pienkoski

et al. 2009

Journal of Biological Chemistry

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Tallysomycins (TLMs) belong to the bleomycin family of anticancer antibiotics. TLMs differ from bleomycins primarily by the presence of a 4-amino-4,6-dideoxy-L-talose sugar attached to C-41 as part of a glycosylcarbinolamide. We previously proposed, on the basis of bioinformatics analysis of the tlm biosynthetic gene cluster from Streptoalloteichus hindustanus E465-94 ATCC 31158, that the tlmK gene is responsible for the attachment of this sugar moiety. We now report that inactivation of tlmK in S. hindustanus abolished TLM A and TLM B production, the resultant ⌬tlmK mutant instead accumulated five new metabolites, and introduction of a functional copy of tlmK to the ⌬tlmK mutant restored TLM A and TLM B production. Two major metabolites, TLM K-1 and TLM K-2, together with three minor metabolites, TLM K-3, TLM K-4, and TLM K-5, were isolated from the ⌬tlmK mutant, and their structures were elucidated. These findings provide experimental evidence supporting the previous functional assignment of tlmK to encode a glycosyltransferase and unveil two carbinolamide pseudoaglycones as key intermediates in the TLM biosynthetic pathway. TlmK stabilizes the carbinolamide intermediates by glycosylating their hemiaminal hydroxyl groups, thereby protecting them from hydrolysis during TLM biosynthesis. In the absence of TlmK, the carbinolamide intermediates fragment to produce an amide TLM K-1 and aldehyde intermediates, which undergo further oxidative fragmentation to afford carboxylic acids TLM K-2, TLM K-3, TLM K-4, and TLM K-5. Tallysomycins (TLMs)3 belong to the bleomycin (BLM) family of glycopeptide antitumor antibiotics (1, 2) (Fig. 1). The BLMs are currently used clinically under the trade name Blenoxane in combination with a number of other agents for the treatment of Hodgkin lymphoma, carcinomas of the skin, head, and neck, and testicular cancers. Early development of drug resistance and dose-dependent pulmonary toxicity are major limitations of BLMs in chemotherapy (3, 4). Structural modifications to this family of natural products are necessary for improvement in efficacy and reduction of toxicity. Although numerous BLM analogs have been synthesized (5, 6), total synthesis remains of limited practical value because of the complex scaffold of this entire family of natural products. Recent cloning and characterization of the BLM, TLM, and zorbamycin biosynthetic gene clusters from Streptomyces verticillus ATCC15003 (7), Streptoalloteichus hindustanus E465-94 (ATCC 31158) (8), and Streptomyces flavoviridis ATCC21892 (9) opened the possibility toward the production of novel BLM analogs via genetic metabolic engineering approaches.TLMs are structurally related to BLMs but differ from BLMs in three ways; (i) the presence of two hydroxyl groups within the aminoethylbithiazole moiety, one of which is conjugated to a 4-amino-4,6-dideoxy-L-talose sugar as part of a glycosylcarbinolamide, (ii) the presence of two series of C-terminal amine moieties with (A series) or without (B series) a ␤-lysine moiety in the subterminal pos...

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Section: Discussionmentioning

confidence: 99%

Functional Characterization of tlmK Unveiling Unstable Carbinolamide Intermediates in the Tallysomycin Biosynthetic Pathway

Wang

Tao

Wendt-Pienkoski

et al. 2009

Journal of Biological Chemistry

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“…In principle, they react with electron-deficient compounds at N 1 [20][21][22][23][24] and electron-rich compounds at N 3 [25][26][27][28]. There can be not only retention of the azide unit but also cleavage of the nitrogenAnitrogen single bond, as in the case of nitrene chemistry [29][30][31][32]. The mechanistically simplest case, addition, has been extensively used in cycloaddition reactions.…”

Section: Introductionmentioning

confidence: 99%

A selective synthesis of enamines versus aziridines

Belei

Bîcu

Jones

et al. 2010

Journal of Heterocyclic Chem

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The reaction of 10‐azidoacetyl‐10H‐phenothiazine with olefinic dipolarophiles depends on the reaction temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The reaction mechanism appears to involve a Michael‐type addition of the nucleophilic N1 azide atom to the olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5‐dihydro‐1,2,3‐triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimination leading to a mixture of enamine and aziridine in 1:3 ratio. J. Heterocyclic Chem., 2011.

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“…16 (e) Rearrangement -hydrolysis of a-silylallyl amides. 17 The N-acyl hemiaminal can be synthesized by oxidative decarboxylation from a suitable N-acyl-a-amino acid, 12a by acylation of a protected hemiaminal 18 or in a direct fashion by reaction of an aldehyde with an amide anion. 19 In this paper we present our own studies towards the synthesis of unsaturated enamides.…”

Section: Introductionmentioning

confidence: 99%